3,5-substituted-1,2,4-oxadiazole inner quaternary ammonium salts

ABSTRACT

New antimicrobial agents of the formula   WHERE R1 includes halophenyl, loweralkyl, phenyl, nitrophenyl, dinitrophenyl, nitrofuryl, and nitrothienyl; R2 includes hydrogen and loweralkyl; and Nhet includes a heterocyclic moiety bonded through a nitrogen thereof which is sufficiently basic to form quaternary ammonium salts.

United States Patent [191 Von Esch et al.

[ 1 Apr. 3, 1973 [54] 3,5-SUBSTITUTED-l,2,4-OXADIAZOLE INNER QUATERNARY AMMONIUM SALTS [75] Inventors: Anne Mary Von Esch, North Chicago; Aldo Joseph Crovetti,

Lake Forest, both of III.

[73] Assignee: Abbott Laboratories, North Chicago, Ill.

[22] Filed: Oct. 30, 1970 21 Appl. No.: 85,747

[52] US. Cl .f26ll/296R, 260/256.4 B, 260/286 Q, 260/288 R, 260/295 R, 260/295 S, 260/302 A, 260/302 I-I, 260/307 G, 424/251,

51 Int. Cl. ..C07d 31/42 [58] Field of Search ..260/296 R, 294.8 D

[56] References Cited v UNITED STATES PATENTS I 3/1972 Crovetti et al. ..260/247.5 R

OTHER PUBLICATIONS Klingsberg, Pyridine and Derivatives, Part Two, Interscience Publishers, Pages 4 & 5, (1961) QD 401K5 C.2 w

Elderfield, Heterocyclic Compounds, Vol. I, Wiley Publishers, Pages 6l2-l3; (1950) OD 400 E4 CA Primary Examiner-Alan L. Rotman Attorney-Robert L. Niblack [57] ABSTRACT New antimicrobial agents of the formula 4 Claims, No Drawings 3 ,S-SUBSTITUTED- l ,2,4-OXADIAZOLE QUATERNARY ANEMONIUM SALTS DISCLOSURE OF THE INVENTION This invention relates to new compounds having antimicrobial utility and which have the formula R1-(IIJ-IUI o-o wherein R is loweralkyl, phenyl, nitrop enyl, dinitrophenyl, nitrofuryl, and nitrothienyl; 2 is hydrogen and loweralkyl; and N is a heterocyclic moiety bonded to the carbon atom on the 5-position of the oxadiazole through a nitrogen atom thereof, which nitrogen is sufficiently basic to quatemize. Such groups that are suitable include pyridinyl, halo and loweralkyl substituted pyridinyl; pyrimidinyl, halo and loweralkyl substituted pyrimidinyl, quinolinium, halo and loweralkyl substituted quinolinium, isoquinolinium, halo and loweralkyl substituted isoquinolinium, thiazolium, isothiazolium and loweralkylthiazolium.

As used herein, the term loweralkyl is intended to include those alkyl groups having-from 1 to 4 carbon atoms, e.g., methyl, ethyl, propyl and butyl. The term halo is meant to include halogen substitutions wherein the halogen substituent is chlorine, bromine, or iodine.

The novel salts of this invention which are described below in detail possess valuable antibiotic activity against organisms such for example as Staphylococcus aureus. Furthermore, activity has been established for a number of these new compounds (as shown below in Table II) against the pathogenic fungi of the genus Trichomona especially T. vaginalis.

These new compounds are utilized as the inner quaternary salt, and being such are somewhat water soluble, at least more so than non-salt organic compounds of an equivalent molecular weight. They may be used in human and veterinary medicine in the form of pharmaceutical compositions containing one or more pharmaceutical carriers or excipients suitable for example, for oral, topical, rectal, intravaginal ,or

parenteral administration. They may be used alone or.

together with other medicinal agents. The compositions are preferably in unit dosage form: and each dosage unit preferably contains 0.5 to 500 m'g. of the active compound, advantageously 5 to 250 mg. for example.

For administration as solid oral preparations such as tablets or capsules, conventional carriers may be employed, for example, gelatin, lactose, starch, talc, magnesium stearate, hydrogenated oils, polyglycols, etc. The compositions may also take the form of liquid oral preparations for ingestion such as solutions, syrups, elixirs, emulsions, etc., which may contain suspending, emulsifying, stabilizing and preserving agents and may also contain acceptable sweetening, flavoring or coloring agents. The compounds may be prepared for local application to the-mucous membranes of the nose and throat and may take the form of liquid sprays or powder insufilation's, nasal drops, throat paints or similar preparations. Formulations for external applications may be prepared in oily, aqueous or powdered media in the form of conventional skin paints, lotions,

creams, ointments, aerosols, dusting powders, etc. Suppositories and pessaries may contain a conventional base, e.g., oil of theobroma, polyglycols, glycogelatin advantageously in the following manner. A compound H of the formula Rial is admixed with N where R and N are as hereinbefore defined, and an appropriate acid anhydride. By appropriate acid anhydride, it is meant that if- R is intended to be hydrogen, then a mixed acetic-formed anhydride should be used, and if R is to be isopropyl, then 2,2-dimeth'yl-acetic anhydride should be employed. While the reaction can be carried out without the use of additional solvent,- preferably an inert solvent such as nitromethane, ethanol or aqueous dimethylsulfoxide is used to insure a more complete reaction with higheryields, By the term inert solvent, is meant a solvent that is not reactive toward reactants or products.

The reaction can be carried out at the reflux temperature of the admixture; yet it is preferred that the reaction temperature bemaintained between 257 5 C. The course of the reaction can easily be followed by observing the formation of product which is a brightly colored solid. After reaction is deemed complete, which is usually the case after 12 hours, the solid product is collected and washed, for example with cold, i.e., less than 0 C. ethanol. v

The following specific examples will further serve to illustrate this invention.

I Example 1 In this method of preparation, the reactants act as mutual solvents, no additional solvent being added. Thus, 9.2 g. of 5-chloromethyl-3-(5-nitro-2-furyl)- 1,2,4-oxadiazole was dissolved in a mixture of 10 ml. of acetic anhydride and 25 ml. of pyridine. The solution was heated overnight at 55 C. In the course of the reaction, the product crystallizes as abright yellow solid. The compound was filtered and washed with ethanol. The yield is 12.5 g., m.p. 265 C (dec). For analysis the 7 compound can be recrystallized from nitromethane or ethanol.

Analysis Calcd. for C I-1 N 0 C, 53.51%; H, 3.21%; N, 17.82% Found: C, 53.24%; H, 3.22%; N, 17.83

Example 2 In this preparation, additional solvent herein being acetonitrile is added. Thus, 5.0 5. (0.0218 mole) of 5- chloromethyl-3-( 5-nitro-2-furyl l ,2,4-oxadiazole, 2.03 g. (0.0218 mole) of 4-methylpyridine, 2.80 g. of

acetic anhydride in 25 ml. acetonitrile heated at reflux for 2 hours. The reaction is cooled, the product filtered, washed with acetonitrile and alcohol successive- 5 ly. After having been dried, there was about 3 g. of crude product having a melting point of greater than 300 C.

Ex. M.P. in Solvent [or ro- Percent No. R\ Ni, R: C. crystallization yield 3 (H EB CII; 240-242 Ethanol. 73.3

l--." Q (BN5 E -CH; 196 do. 82,6

5. Same as above CH K 272-277 Nltromethane. 71. 5

IIIO: d0 OH; 260 Ethanol 75. 5 6"-.- f E 7 do -CH; 248-250 do 83.3

NOr-

8. .do CII 1 265 Nitromethane 97.3

9. Same as above "do CH:CH; 243-245 do 98 10 do do -OH;OH;CH 253 Ethanol 80.5

11. .d0 @fi CH 247-249 d0 72 12. do; Giq CH 255-258 Nitromethane. 50

13- do 63 'CH; 300 do 73 -N CH:!

14 d0 CH3 ClIq CH3 235 do 37 l5 do (3H3 CI'IJ 245-247 do 89 6B N -CI'I.1

lb "d0 (71h -OI[, 205 ...do 67 17 10 CH3 (/II 245-247 d0 (19 18 do (Ill-l3 CII 290 .-.do JU B// CII1 19 d0 CH3 CH1 300 Ethanol 51.5

8 l I do Clh 265 NOzL Ex. M.P.ln Solvent for re- Percent No. R Nb" R2 C. crystallization yield d0 A CH; I 255 Nltromethane 41. 8

c113 300 d0 .A 24' -0m 247-240 Mao 63.7

,CHa 1 283-284 DMSO-hHzO.....

GHa 270 DMSO+I-IO 85 M.P. in So vent for Percent Ex No R Nhoc R2 C. recrystallization yield 3 CH3 6 CHJ 240-242 Ethanol 73.3

4 Q CHn 196 do 82.6

5 NO Q Same as above OH; 272-277 Nltromethanenh, 71. 5

6 Nil); ....d0 CH; 260 Ethanol H 75.5

7 U do CIL. l 248-250 .do 83.3

Nor-L Nllrom ethancflnl v 97.3

CllaUHg I 243-245 (l0 l8 I) Same as above 0 .d0 .d0 CIIQCIHCIH' 253 Ethanol .l 80.5

11 d0 ClIz; 247-240 d0 v 72 12 do QN -CH 265-2158 Nitrolnethaue..

l3 "do Salmons ubov0. -011; 300 7 14 .410 011.1 nn oun '23s '37 \LZT 15 ..(l0 CH3 (JH; 1 145-247 d0 B CII;

l6 do $H; --CH 295 do 67 Found: C, 38.16;l-l, l .7 7; N, 1 9.75 7 The compounds of this invention have demonstrated in vitro utility against Staphylocossus aureus Smith and such activity is illustrated in Table I in which the minimum inhibitory concentration is set forth in parts per million.

TABLE I Compound of Minimum Inhibitory Example Concentration Table [1 illustrates the in vitro activity of the compounds of this invention against Trichomonas vaginalis in parts per million.

I; Q n I H M.P. in So vent for Percent Ex. N0. R1 Nhet R2 C. recrystallization yield 17 d0 CH; 0113 245-247 do.- 00

18 "do 01-1., -CH;, 200 .do 00 do CH; CI'IJ 300 Ethanol 51.5

69 I\% CH3 20 d0 A CH.1 255 Nltr0methan0. 41. 8

-N ea 21 ..do 0 -01IJ 1 300 do 24 CI-Ia 22 do ea CH3 247-240 tlO 03.7

I Br

23 .do ea OH; 233-234 DMSO+H1O 45 l GONHz 24 "do Same as above CH; 1 270 DMSO-l-HzO 85 l Decomposed.

The 5-chloromethyl-3-(3,5-dinitrophenyl)-1,2,4-ox- TABLE II adiazole, which is used to prepare the compound of this invention disclosed in Example 6, is prepared in the fol- Compound of Minimum Inhibitory l Example Concentration owing manner. 7 100 10 g. of 3,5-dinitrophenylamidoxime is refluxed in 20 0 100 ml. of chloroacetylchloride for two hours. The excess 1; acid chloride is removed under reduced pressure. The 19 o oily solid is then suspended in 50 ml. of butanol and 20 refluxed for six hours. Upon cooling, the product w crystallizes from the solvent. M.P. 1268 C. e Analysis Calcd. for C H ClN O c, 37.99; H, 1.78; H, The compound of the formula 63 g N CCNber R1(3 -o in which N is selected f rB rn the group consisting of 

2. A compound according to claim 1 in which Nhet is pyridinium.
 3. A compound according to claim 1 in which Nhet is loweralkyl substituted pyridinium.
 4. A compound according to claim 1 wherein Nhet is pyridinium, R1 is 5-nitro-2-furyl and R2 is methyl. 